Defects in transcriptional regulation underlie numerous disease states, including cancer. See, e.g., Nebert (2002) Toxicology 181-182:131-41. A major goal of current strategies for correcting such defects is to achieve sufficient specificity of action. See, e.g., Reid et al. (2002) Curr Opin Mol Ther 4:130-137. Designed zinc-finger protein transcription factors (ZFP TFs) emulate natural transcriptional control mechanisms, and therefore provide an attractive tool for precisely regulating gene expression. See, e.g., U.S. Pat. Nos. 6,607,882 and 6,534,261; and Beerli et al. (2000) Proc Natl Acad Sci USA 97:1495-500; Zhang et al. (2000) J Biol Chem 275:33850-60; Snowden et al. (2002) Curr Biol 12:2159-66; Liu et al. (2001) J Biol Chem 276:11323-34; Reynolds et al. (2003) Proc Natl Acad Sci USA 100:1615-20; Bartsevich et al. (2000) Mol Pharmacol 58:1-10; Ren et al. (2002) Genes Dev 16: 27-32; Jamieson et al. (2003) Nat Rev Drug Discov 2:361-368). Accurate control of gene expression is important for understanding gene function (target validation) as well as for developing therapeutics to treat disease. See, e.g., Urnov & Rebar (2002) Biochem Pharmacol 64:919-23.
However, for many disease states, it may be that these proteins, or any other gene regulation technology, will have to be specific for a single gene within the genome—a challenging criterion to meet given the size and complexity of the human genome. Indeed, recent studies with siRNA (Doench et al. (2003) Genes Dev 17:438-42; Jackson et al. (2003) Nat Biotechnol 18:18) and antisense DNA/RNA (Cho et al. (2001) Proc Natl Acad Sci USA 98:9819-23) have fallen far short of obtaining single-gene specificity; illuminating the magnitude of the task of obtaining exogenous regulation of a single specific gene in a genome, e.g., the human genome.